Autoimmune ovarian disease (AOD) is a poorly understood clinical entity wherein immune-mediated destruction of oocytes leads to premature ovarian failure and infertility. The mechanisms of pathogenesis and antigens targeted remain largely unknown, and directed therapies for intervention are lacking. We have generated a spontaneous disease model to study AOD using mice deficient for the Autoimmune Regulator (AIRE) gene, a gene first identified in the human Autoimmune Polyglandular Syndrome (APS) type 1. Like patients with APS 1, aire-deficient mice develop disease of multiple organs, including the ovary, due to a breakdown in central tolerance. Autoimmunity is manifested by development of antigen-specific autoantibodies, organ infiltration, and transfer of disease by lymphocytes from affected aire KO mice. We have demonstrated that the primary defect in the aire-deficient animals is a loss of the ability of epithelial cells within the thymus to present and tolerize developing T cells to self-antigens. As a result autoreactive lymphocytes can escape into the periphery with potential for auto-reactivation within target organs with destruction of self-tissues. In a susceptible strain of aire KO females, I see 100% incidence of oophoritis on histology as well as circulating autoantibodies to ovarian tissue. This presents a valuable spontaneous disease model in which to identify ovarian antigens. Thus, I hypothesize that AOD arises in aire KO females due to failure of negative thymic selection of ovarian reactive T cells and that these autoreactive T cells reflect a lack of appropriate aire-dependent ovarian antigen expression in the thymus. To investigate this hypothesis, I propose the following specific aims. Aim 1: To characterize the humoral and cell-mediated immunopathogenesis of AOD in aire KO mice. Aim 2: To identify ovarian autoantigens targeted in aire-deficient mice. Aim 3: To establish clinical correlations of disease markers in AOD. By identifying the ovarian component that initiates attack of self, I will better understand the common mechanisms that maintain immune tolerance and normally protect our tissues from many forms of autoimmune disease. Knowledge of the disease-inciting antigen could enable improved testing for the diagnosis and prognosis of autoimmune ovarian disease. Finally, identifying the causative ovarian antigen may provide a potential therapeutic target for treatment and prevention of a significant cause of human ovarian failure and infertility.